Therapeutic potential of the dual peroxisome proliferator activated receptor (PPAR)α/γ, agonist aleglitazar in attenuating TNF-α-mediated inflammation and insulin resistance in human adipocytes

Adipose tissue inflammation is a mechanistic link between obesity and its related sequelae, including insulin resistance and type 2 diabetes. Dual ligands of peroxisome proliferator activated receptor (PPAR)alpha and gamma, combining in a single molecule the metabolic and inflammatory-regulatory properties of alpha and gamma agonists, have been proposed as a promising therapeutic strategy to antagonize adipose tissue inflammation. Here we investigated the effects of the dual PPAR alpha/gamma agonist aleglitazar on human adipocytes challenged with inflammatory stimuli. Human Simpson-Golabi-Behmel syndrome (SGBS) adipocytes were treated with aleglitazar or - for comparison - the selective agonists for PPAR alpha or gamma fenofibrate or rosiglitazone, respectively, for 24 h before stimulation with TNF-alpha. Aleglitazar, at concentrations as low as 10 nmol/L, providing the half-maximal transcriptional activation of both PPAR alpha and PPAR gamma, reduced the stimulated expression of several pro-inflammatory mediators including interleukin (IL)-6, the chemokine CXC-L10, and monocyte chemoattractant protein (MCP)-1. Correspondingly, media from adipocytes treated with aleglitazar reduced monocyte migration, consistent with suppression of MCP-1 secretion. Under the same conditions, aleglitazar also reversed the TNF-alpha-mediated suppression of insulin-stimulated ser473 Akt phosphorylation and decreased the TNF-alpha-induced ser312 IRS1 phosphorylation, two major switches in insulin-mediated metabolic activities, restoring glucose uptake in insulin-resistant adipocytes. Such effects were similar to those obtainable with a combination of single PPAR alpha and gamma agonists. In conclusion, aleglitazar reduces inflammatory activation and dysfunction in insulin signaling in activated adipocytes, properties that may benefit diabetic and obese patients. The effect of aleglitazar was consistent with dual PPAR alpha and gamma agonism, but with no evidence of synergism. (C) 2016 Elsevier Ltd. All rights reserved.